Stroke is the third most frequent cause of mortality in western society. Recent progress in the field of ischernic stroke has shown that thrombolysis treatment increases survival and reduces disability, but that early intervention is the key to successful therapeutic outcome. Because treatment also poses risks in terms of increased chance of hemorrhage, it is essential to determine whether reversible or irreversible damage has occured during and after ischernic periods. Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) hold great promise for noninvasive assessment of brain damage. In addition to assessing large- vessel and small-vessel perfusion using MR angiography (MRA) and dynamic contrast imaging, respectively, the occurrence of a mismatch between diffusion and perfusion abnormalities has been used as an indicator for need for treatment. Even though this has met with some success to extend the treatment window from 3 to 6 or even more hours post-ictus, the exact meaning of the diffusion and perfusion deficits remains a point of discussion and there is a general consensus that a multi-parameter assessment of different flow and metabolic zones in the ischernic region would enhance the specificity of the MR assessment. The ultimate goal of our research is to establish a set of MRI criteria that will allow such an assessment. Towards this end our research has focused on the development of new functional imaging methods that can quantitatively assess tissue status when neurologic recovery is still possible. Based on results obtained in the previous grant period, we have designed the following hypotheses for ischernic stroke: (1) The area of hypoperfusion that has reduced pH predicts the area that will go to infarction if no treatment is initiated; (2) The area of increased microvascular cerebral blood volume (CBV) is a marker for tissue at risk of infarction. (3) quantification of oxygen extraction fraction (OEF) can predict the risk for tissue infarction based on the principle of flow thresholds. Our corresponding three aims are to develop new noninvasive MRI methodologies that are sensitive to changes in pH, CBV, and OEF and to subsequently test our three hypothesis on rat brain models of transient focal ischemia. Our fourth and final aim is to implement the new technologies on the clinical scanner and to optimize their use for a fast and specific clinical stroke exam.